Thienamycin absolute stereochemistry

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

Since the first report by Bergbreiter and Newcomb in 1980 [72] on the utilization of lithium enolates of esters in place of Reformatsky reagents for the construction of the azetidinone ring (Fig. 4), several research groups have applied such approach to the synthesis of carbapenem compounds. Most notably, the recent review by Georg [5g] on the synthesis of thienamycin and related P-lactams delineated the most recent advances in the P-lactam field and focuses great attention on the utilization of optically active esters of 3-hydroxy-butyric acid for an effective control of the relative and absolute stereochemistry at the carbon atoms T and 3 of the 3-(l -hydroxyethyl)azetidin-2-one 132. Inversion of the configuration at the hydroxyethyl side chain by Mitsunobu s reaction [42] and further elaboration of the peripheral functionalities leads to the formation of a variety of carbapenem precursors. 

When optically active enamine derivatives are used as substrates, full control of absolute stereochemistry is feasible, and the process is appUcable to the synthesis of a known precursor of (+)-thienamycin in very high optical yieldf" (Scheme 20). 

Fluorothreonine. In 1986 a second Streptomyces species capable of the biosynthesis of fluorinated compounds was identified (24). In the course of studies with Streptomyces cattleya to improve the yield of the 6-lactam antibiotic, thienamycin, it was discovered that when fluoride was present in tiie culture medium both fluoroacetate 1 and 4-fluorothreonine 6 accumulated in millimolar concentrations during fermentation. 4-fluorothreonine is the only naturally ocurring fluorinated amino acid known. When 4-fluorothreonine was initially isolated (24) the absolute stereochemistry of 4-fluorothreonine was predicted to be analogous to L-threonine. We have recently confirmed this by asymmetric synthesis (25) and demonstrated that natural 4-fluorothreonine has the (25, 3S) configuration. The... 

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